The invention relates to the further characterization of the structure and function of the isolated oligopeptide obtained from Entamoeba histolytica, previously identified as monocyte locomotion inhibitory factor (“MLIF”). This characterization has led to the discovery of a family of oligopeptides useful for the treatment of a variety of inflammatory conditions, such as rheumatoid arthritis and psoriasis.
Entamoeba histolytica, in motile form, is a dynamic pleomorphic protozoon which is common in Mexico, Africa and Asia. E. histolytica is an invasive parasite having a simple cytoplastic structure. Infection by pathogenic E. histolytica may result in the invasion of several organs and tissues in humans. The most commonly affected organs are the colon and the liver. Less frequently, the parasite may invade the lungs, the brain, the skin and the genitalia.
E. histolytica is known to cause liver abscesses and other lesions in the human population. In amoebic liver lesions, a moderate inflammation occurs characterized by the presence of neutrophils, epithelioid cells and macrophages, with less abundant neutrophils, lymphocytes and plasma cells. It has been observed that although the early stages of parasitic invasion are characterized by acute inflammation in which even some eosinophilic leukocytes occur, the advanced stages are characterized by a scarcity of inflammation. Moreover, livers with such hepatic abscesses have been found to regenerate perfectly without a trace of scarring following effective treatment with appropriate medicines. Sepulveda, B. et al., Immunology of Parasitic Disease, ppg. 170-191 (1982).
The supernatant fluid of axenically grown E. histolytica has been shown to inhibit chemotaxis, chemokinesis and the random mobility of human mononuclear phagocytes. Human polymorphonuclear neutrophil phagocyte locomotion is apparently unaffected. It has been postulated that the inhibition of human mononuclear phagocytes by the entamoeba product contributes to the lack of inflammatory reaction observed in the advanced stages of invasive amoebiasis, and consequently and auspiciously, to the lack of scar tissue formation upon healing of amoebic lesions through regeneration. Kretschmer, R. R. et al., Parasite Immunology, 7, Pages 527-543 (1985). See also Rico, G. et al., Archives of Medical Research, 28(5), pages 235-236 (1997). This product may also constitute a defensive factor of the amoeba which is capable of reducing or blocking the inflammatory response of the host.
In basic terms, inflammation is a localized, protective response elicited by a foreign antigen, or by an injury or destruction of tissue. Inflammation occurs when tissues are injured by viruses, bacteria, trauma, chemicals, heat, cold, or any other harmful stimuli. In such instances, the classic weapons of the immune system (T cells, B cells, macrophages) interface with cells and soluble products which arc mediators of inflammatory responses (neutrophils, cosinophils, basophils, macrophages, cytokines, kinin and coagulation systems, and the complement cascade).
A typical inflammatory response is characterized by (i) migration of leukocytes at the site of the injury or trauma; (ii) specific and nonspecific recognition of foreign antigens mediated by B and T lymphocytes, macrophages and the alternative complement pathway; (iii) amplification of the inflammatory response with the recruitment of specific and nonspecific effector cells by complement components, lymphokines and monokines, kinines, arachidonic acid metabolites, and mast cell/basophil products; and (iv) macrophage, neutrophil and lymphocyte participation in antigen destruction, with the ultimate removal of antigen particles or injured tissue by phagocytosis. Diseases associated with such inflammatory responses include rheumatoid arthritis, lupus and psoriasis. The rejection of allografts following organ transplantation also involves these inflammatory responses.
NF-κβ protein is a transcription factor that is activated by pro-inflammatory signals. The NF-κβ signaling pathway is a conserved evolutionary system that is essential for host defense. The system triggers and regulates innate immunity, and co-signals adaptive immunity in humans. The members of the NF-κβ system form homodimers and heterodimers (p50/p50 and p50/p65) which, when linked to natural up-stream NF-κβ inhibitors, such as Iκβ's, fail to translocate to the nucleus. When the Iκβ's are degraded in the proteosome, the NF-κβ homodimers and heterodimers are set free to translocate into the nucleus and to start the transcription of many critical genes. See FIG. 1 below. NF-κβ p65/p50 heterodimers are the leading gene transcriptors, while p50/p50 homodimers act as inhibitors.
Although inflammation is an essential defense mechanism against infection, it is nevertheless appropriate to consider approaches to modulate or directly inhibit the inflammation if failure to do so would lead to severe and irreversible damage to organs and tissue, including scarring.
It will therefore be readily appreciated that a continuing need exists to develop improved treatments for inflammatory diseases, as well as treatments for conditions of moderate and extreme inflammation.